IV rt-PA (Activase) became the first scientifically proven and FDA-approved therapy for acute ischemic stroke (AIS) in 1996. Despite the advance that rt-PA represents for acute stroke therapy, 50% of patients treated with rt-PA have physical disability at three months, and intravenous rt-PA alone opens only approximately 30-40% of arteries after one hour of treatment. Because time is an important determinant of outcome in acute ischemic stroke, new combination approaches to improve the speed and success of early arterial recanalization are necessary for treatment of AIS. The addition of Glycoprotein (GP) lib/I I la antagonists to fibrinolytic regimens, increase both the speed of arterial recanalization and the percentage of patients with open arteries in acute myocardial infarction. GP llb/llla antagonists in acute Ml have not been associated with increased rates of intracerebral hemorrhage. The potential to augment fibrinolysis in AIS led us to perform the Combined approach to Lysis utilizing Eptifibatide And Rt-PA (CLEAR) stroke trial. That trial demonstrated that the combination of low dose rt-PA plus eptifibatide can be safely given to AIS patients within 3 hours of symptom onset. Based on the notable safety of the combination in CLEAR but the lack of a signal of efficacy compared with standard dose rt-PA we propose to perform the CLEAR-Enhanced Regimen (CLEARER) stroke trial. This multi-center, double-blind, randomized safety study is designed to provide data concerning the risks and benefits of combining a GP llb/llla antagonist, eptifibatide, with low-dose intravenous rt-PA in 100 AIS patients. Patients will be randomized to a combined intravenous low-dose rt-PA and eptifibatide regimen, or standard dose (0.9 mg/kg) rt-PA in a 3 to 1 ratio. This will result in a total of 75 patients treated with a combined regimen, and 25 patients treated with standard dose IV rt-PA alone. Patients treated with eptifibatide and rt-PA will be compared to patients treated with the control regimen of standard dose rt-PA in the present study. The Primary Specific Aims for this Study are: 1. To obtain reliable estimates of the safety of an enhanced dosing regimen of eptifibatide in combination with 0.6 mg/kg of rt-PA in acute stroke patients in whom treatment is begun within three hours of symptom onset. 2. To determine if the estimated efficacy of combination therapy in acute ischemic stroke warrants proceeding to a large Phase III randomized trial. 3. To obtain data that will allow us to determine the sample size needed for a potential Phase III trial comparing the combination to standard dose rt-PA.